Role of the ABCG8 19H risk allele in cholesterol absorption and gallstone disease

Abstract

BackgroundGallstone disease is associated with p.D19H of ABCG8 as well as alterations of cholesterol and bile acid metabolism. However, molecular mechanisms have not been fully elucidated. It is important to understand the link between the sterol transporters ABCG5/8 and NPC1L1 and intestinal cholesterol absorption as well as de novo synthesis in gallstone patients stratified according to 19H risk allele. Moreover, the functional importance of the 19H variant on intestinal ABCG8 feature remains to be clarified.MethodsMeasurements of serum surrogate markers of cholesterol absorption (plant sterols: sitosterol, campesterol) and synthesis (cholesterol precursor: lathosterol) were carried out by gas chromatography/mass spectrometry (GC/MS). For expression studies, total RNA was isolated from 168 ileal biopsies of study participants with (34) and without gallstone disease (134). Messenger RNA was measured by LightCycler real-time PCR. Genomic DNA was obtained from blood leukocytes. Genotype frequencies of p.D19H were established using MALDI-TOF mass spectrometry.ResultsCompared to controls, cholesterol absorption but not synthesis in gallstone carriers was diminished by about 21% based on low serum sitosterol (P = 0.0269) and campesterol (P = 0.0231) to cholesterol ratios. D19H was found to be significantly associated with gallstones (odds ratio [OR] = 2.9, P = 0.0220, 95% confidence interval [CI]:1.22-6.89), particularly in the overweight cohort (OR = 3.2, P = 0.0430, 95% CI:1.07-9.26). Cholesterol absorption was about 24% lower in individuals carrying p.D19H compared to wild type (Psitosterol = 0.0080, Pcampesterol = 0.0206). Moreover, irrespective of phenotype, carriers of p.D19H displayed a significant lower absorption than carriers of the major allele. The most pronounced effect on cholesterol absorption ratio was observed for serum campesterol levels (wild type controls to mutated controls 28%, P = 0.0347 and wild type controls to gallstone carriers with 19H allele 37%, P = 0.0030). Notably, ABCG5/8 and NPC1L1 expression was similar in gallstone carriers and controls regardless of p.D19H presence.ConclusionsBoth gallstone disease and p.D19H of ABCG8 are associated with diminished cholesterol absorption. However, p.D19H is not responsible for the differences in small intestinal sterol transporter expression.

Serum Plant Sterols Associate with Gallstone Disease Independent of Weight Loss and Non-Alcoholic Fatty Liver Disease

“…Our findings that low plant sterol levels in individuals with GD were observed both before and after obesity surgery, in those with and without previous LCC, and independent of NAFLD,supporttheconclusionthatcholesterolandplantste-rolmetabolismareprimarilyalteredinGD.Theseresultsarein line with the results from Krawczyk et al [11] who also found that serum sterols were lower in patients with GD compared to those without GD. These results also support the idea that low levelsofserumplantsterolsarerelatedtoGDitself,potentially partlyduetogeneticregulationbyABCG5/8genes [17,19,20,31].…”

“…As plant sterols are not synthesized in the human body, their serum levels have been used to estimate the function of hepatic and intestinalcholesterol transporters [14]. Interestingly, variants in the ABCG5/8 transporters that associate with changes in sterol transport alsocontribute to cholesterol gallstone formation suggesting a common etiology [17][18][19][20].…”

Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals

“…The quality and quantity controls of isolated material were assessed as reported. 22 Blood samples (3-5 ml) were used for determination of total serum cholesterol and triglyceride levels as well as for bile acid metabolism profiling (measurements of bile acid synthesis markers, serum bile acid, and FGF19 concentrations). Serum triglycerides and cholesterol levels were analysed by standard clinical tests.…”

Distribution of the ATP-binding cassette transporter ABCG8 IVS1-2A>G genotype and clinical characteristics of gallbladder patients in Northeastern Mexico: A pilot study

“…In fact, mutations and polymorphisms in ABCG5 and ABCG8 genes were identified in these patients (7). In other studies, the involvement of ABCG8 gene polymorphisms D19H and Y54C/T400K have been associated with the development of gallstone disease in German, Romanian, Scandinavian, Chinese and Indian populations, among others (8,9). Recently, a genome-wide association study meta-analysis conducted by Joshi et al (10) revealed the association of two ABCG8 gene polymorphisms, rs11887534 and rs4245791, with the risk of developing gallstones.…”